Disease activity and treatment efficacy using patient-level Psoriasis Area and Severity Index scores from tildrakizumab phase 3 clinical trials.

BACKGROUND: It is unclear whether primary efficacy outcomes in plaque psoriasis clinical trials represent residual disease during treatment. OBJECTIVES: To evaluate supplementing dichotomous efficacy with residual disease activity. METHODS: This post hoc analysis used pooled, patient-level data after tildrakizumab 100 mg (N = 616) or placebo (N = 309) treatment from reSURFACE 1/2 (NCT01722331/NCT01729754) phase 3 clinical trials of patients with moderate to severe plaque psoriasis. RESULTS: Median baseline Psoriasis Area and Severity Index (PASI) was 17.9 for patients receiving tildrakizumab 100 mg. At Week 12, median PASI was 2.9, whereas dichotomous PASI 90 response rate was 36.9%, and absolute PASI <5.0, <3.0, and <1.0 were 64.0%, 50.8%, and 23.3%, respectively. At Week 28, median PASI was 1.7, whereas PASI 90 response rate was 51.9%, and absolute PASI <5.0, <3.0, and <1.0 were 75.3%, 62.8%, and 38.0%, respectively. Dermatology Life Quality Index and PASI scores were correlated through Week 28 (r = 0.51, p ≤ .0001). CONCLUSIONS: Disease activity was more reliably estimated by PASI scores than percentage PASI improvement; this may partially explain efficacy disparities between clinical trials and practice. These results suggest supplementing dichotomous PASI improvement with PASI scores and consideration of patient treatment goals could facilitate clinical decisions.

Position statement for a pragmatic approach to immunotherapeutics in patients with inflammatory skin diseases during the coronavirus disease 2019 pandemic and beyond.

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, a novel RNA virus that was declared a global pandemic on 11 March 2020. The efficiency of infection with SARS-CoV-2 is reflected by its rapid global spread. The SARS-CoV-2 pandemic has implications for patients with inflammatory skin diseases on systemic immunotherapy who may be at increased risk of infection or more severe infection. This position paper is a focused examination of current evidence considering the mechanisms of action of immunotherapeutic drugs in relation to immune response to SARS-CoV-2. We aim to provide practical guidance for dermatologists managing patients with inflammatory skin conditions on systemic therapies during the current pandemic and beyond. Considering the limited and rapidly evolving evidence, mechanisms of action of therapies, and current knowledge of SARS-CoV-2 infection, we propose that systemic immunotherapy can be continued, with special considerations for at risk patients or those presenting with symptoms.

Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2).

BACKGROUND: Tralokinumab, a fully human monoclonal antibody, specifically neutralizes interleukin-13, a key cytokine driving peripheral inflammation in atopic dermatitis (AD). In phase II studies, tralokinumab combined with topical corticosteroids provided early and sustained improvements in AD signs and symptoms. OBJECTIVES: To evaluate the efficacy and safety of tralokinumab monotherapy in adults with moderate-to-severe AD who had an inadequate response to topical treatments. METHODS: In two 52-week, randomized, double-blind, placebo-controlled, phase III trials, ECZTRA 1 and ECZTRA 2, adults with moderate-to-severe AD were randomized (3 : 1) to subcutaneous tralokinumab 300 mg every 2 weeks (Q2W) or placebo. Primary endpoints were Investigator's Global Assessment (IGA) score of 0 or 1 at week 16 and ≥ 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16. Patients achieving an IGA score of 0 or 1 and/or EASI 75 with tralokinumab at week 16 were rerandomized to tralokinumab Q2W or every 4 weeks or placebo, for 36 weeks. The trials were registered with ClinicalTrials.gov: NCT03131648 and NCT03160885. RESULTS: At week 16, more patients who received tralokinumab vs. placebo achieved an IGA score of 0 or 1: 15·8% vs. 7·1% in ECZTRA 1 [difference 8·6%, 95% confidence interval (CI) 4·1-13·1; P = 0·002] and 22·2% vs. 10·9% in ECZTRA 2 (11·1%, 95% CI 5·8-16·4; P < 0·001) and EASI 75: 25·0% vs. 12·7% (12·1%, 95% CI 6·5-17·7; P < 0·001) and 33·2% vs. 11·4% (21·6%, 95% CI 15·8-27·3; P < 0·001). Early improvements in pruritus, sleep interference, Dermatology Life Quality Index, SCORing Atopic Dermatitis and Patient-Oriented Eczema Measure were observed from the first postbaseline measurements. The majority of week 16 tralokinumab responders maintained response at week 52 with continued tralokinumab treatment without any rescue medication (including topical corticosteroids). Adverse events were reported in 76·4% and 61·5% of patients receiving tralokinumab in ECZTRA 1 and ECZTRA 2, respectively, and in 77·0% and 66·0% of patients receiving placebo in ECZTRA 1 and ECZTRA 2, respectively, in the 16-week initial period. CONCLUSIONS: Tralokinumab monotherapy was superior to placebo at 16 weeks of treatment and was well tolerated up to 52 weeks of treatment.

Long-term efficacy of certolizumab pegol for the treatment of plaque psoriasis: 3-year results from two randomized phase III trials (CIMPASI-1 and CIMPASI-2).

BACKGROUND: Certolizumab pegol (CZP) is an Fc-free, PEGylated anti-tumour necrosis factor biologic. OBJECTIVES: To report the 3-year efficacy of CZP in plaque psoriasis, pooled from the CIMPASI-1 (NCT02326298) and CIMPASI-2 (NCT02326272) phase III trials. METHODS: Adults with moderate-to-severe psoriasis for ≥ 6 months were randomized 2 : 2 : 1 to CZP 200 mg, CZP 400 mg or placebo, every 2 weeks (Q2W) for up to 48 weeks. Patients entering the open-label period (weeks 48-144) from double-blinded CZP initially received CZP 200 mg Q2W. Patients not achieving ≥ 50% improvement in Psoriasis Area and Severity Index (PASI 50) at week 16 entered an open-label CZP 400 mg Q2W escape arm (weeks 16-144). Dose adjustments based on PASI response were permitted during open-label treatment. Outcomes included PASI 75, PASI 90 and Physician's Global Assessment (PGA) 0/1 responder rates, based on a logistic regression model (missing data imputed using Markov Chain Monte Carlo methodology). RESULTS: In total, 186 patients were randomized to CZP 200 mg Q2W and 175 to CZP 400 mg Q2W. At week 48, PASI 75/90 was achieved by 72·7%/51·3% of patients randomized to CZP 200 mg and 84·4%/62·7% randomized to CZP 400 mg. Patients entering the open-label period at week 48, from blinded treatment, received CZP 200 mg Q2W. At week 144, PASI 75/90 was achieved by 70·6%/48·7% patients randomized to CZP 200 mg and 72·9%/42·7% randomized to CZP 400 mg. At week 16, 72 placebo-randomized patients entered the CZP 400 mg Q2W escape arm; 75.7%/58.5% achieved PASI 75/90 at week 144. CONCLUSIONS: Both CZP 200 mg and 400 mg Q2W demonstrated sustained, durable efficacy, with numerically higher responses for some outcomes with 400 mg Q2W.

Efficacy and safety of risankizumab vs. secukinumab in patients with moderate-to-severe plaque psoriasis (IMMerge): results from a phase III, randomized, open-label, efficacy-assessor-blinded clinical trial.

BACKGROUND: Patients with plaque psoriasis treated with biologic therapies need more efficacious, safe and convenient treatments to improve quality of life. Risankizumab and secukinumab inhibit interleukin-23 and interleukin-17A, respectively, and are effective in adult patients with moderate-to-severe plaque psoriasis but have different dosing regimens. OBJECTIVES: To compare directly the efficacy and safety of risankizumab vs. secukinumab over 52 weeks. METHODS: IMMerge was an international, phase III, multicentre, open-label, efficacy-assessor-blinded, active-comparator study, in which adult patients with chronic, moderate-to-severe plaque psoriasis were randomized in a 1 : 1 ratio to treatment with risankizumab 150 mg or secukinumab 300 mg. Primary efficacy endpoints were the proportions of patients achieving ≥ 90% improvement from baseline in Psoriasis Area and Severity Index (PASI 90) at week 16 (noninferiority comparison with margin of 12%) and week 52 (superiority comparison). RESULTS: In total 327 patients from nine countries were treated with risankizumab (n = 164) or secukinumab (n = 163). Risankizumab was noninferior to secukinumab in the proportion of patients achieving PASI 90 at week 16 [73·8% vs. 65·6%; difference of 8·2%, 96·25% confidence interval (CI)-2·2 to 18·6; within the 12% noninferiority margin] and superior to secukinumab at week 52 (86·6% vs. 57·1%; difference of 29·8%, 95% CI 20·8-38·8; P < 0·001), thus meeting both primary endpoints. All secondary endpoints (PASI 100, static Physician's Global Assessment 0 or 1, and PASI 75) at week 52 demonstrated superiority for risankizumab vs. secukinumab (P < 0·001). No new safety concerns were identified. CONCLUSIONS: At week 52, risankizumab demonstrated superior efficacy and similar safety with less frequent dosing compared with secukinumab.

Efficacy of tildrakizumab by patient demographic and disease characteristics across a phase 2b and 2 phase 3 trials in patients with moderate-to-severe chronic plaque psoriasis.

BACKGROUND: Tildrakizumab is a high-affinity, anti-interleukin-23p19 monoclonal antibody approved for treatment of moderate-to-severe plaque psoriasis. OBJECTIVES: To evaluate the effects of patient demographic and disease characteristics on tildrakizumab efficacy using phase 2b/3 trial data. METHODS: Data from patients who received placebo, or tildrakizumab 100 or 200 mg, in P05495 [NCT01225731], reSURFACE 1 [NCT01722331] and reSURFACE 2 [NCT01729754] were analysed. Patient subgroups were defined by age, sex, race, weight, self-reported psoriatic arthritis, failure of ≥1 traditional systemic treatment and prior biologic use. Percentage of Psoriasis Area and Severity Index (PASI) 75 and 90 responders at Week 12 were compared across treatment arms in each subgroup. Absolute PASI at Weeks 0 and 12 was also determined for each subgroup. RESULTS: Among patients randomized in P05495 (N = 355), reSURFACE 1 (N = 772) and 2 (N = 1090), percentage of PASI 75 and 90 responders were significantly greater for each tildrakizumab dose vs. placebo (P < 0.0001). PASI 75 and 90 responder percentages were numerically greater in patients <65 years of age, bodyweight ≤90 kg, without psoriatic arthritis and with no prior biologic exposure (only PASI 90), vs. their counterparts in corresponding subgroups. There were no clear or consistent differences in efficacy between the other subgroups. Absolute PASI scores were generally similar across subgroups. CONCLUSIONS: Small numerical differences in tildrakizumab efficacy were observed between subgroups defined by patient age and weight, presence of psoriatic arthritis and prior biologic use. These differences were not clinically meaningful; however, analyses of long-term data may be of value. Tildrakizumab efficacy did not differ with respect to patient sex or race, or number of prior failed conventional systemic treatments. Overall, these results suggest tildrakizumab may be appropriate for treatment of moderate-to-severe plaque psoriasis in patients with a range of demographic and disease characteristics.

Adalimumab for nail psoriasis: efficacy and safety over 52 weeks from a phase-3, randomized, placebo-controlled trial.

BACKGROUND: Few clinical trials have evaluated long-term treatment of nail psoriasis with biologics. OBJECTIVE: Safety and efficacy of adalimumab [ADA; Humira AbbVie Inc, North Chicago, IL, USA)] long-term treatment (52 weeks) was evaluated in a phase-3, randomized trial in patients with moderate-to-severe plaque psoriasis and concomitant moderate-to-severe fingernail psoriasis. Results from the first 26 weeks (Period A) have been reported. METHODS: Patients receiving 40 mg ADA every other week or placebo in Period A, continued with or switched to 40 mg ADA every-other-week treatment in the subsequent 26-week open-label extension (OLE) period. Main efficacy evaluations were ≥75% improvement in total-fingernail modified Nail Psoriasis Severity Index (mNAPSI 75) and achievement of Physician's Global Assessment for Fingernail Psoriasis of clear or minimal disease (PGA-F 0/1) with a ≥2-grade improvement from baseline, across the trial for patients who continued ADA from Period A through the OLE (Continuous-ADA Population). Safety was evaluated during the OLE and for patients receiving ADA at any time during the study (All-ADA Population). RESULTS: Of the 217 patients initially randomized in Period A, 188 (86.6%; 94 in each treatment group) entered the OLE after completion of or early escape from Period A. For the Continuous-ADA Population (N = 109), endpoint achievement rates improved from OLE entry (Week 26) to Week 52, including total-fingernail mNAPSI 75 (47.4-54.5%); PGA-F 0/1 (51.1-55.6%) and total-fingernail mNAPSI = 0 (6.6-17.9%). Serious adverse event and serious infection rates for the All-ADA Population (N = 203) were 6.9% and 3.4%, respectively. CONCLUSIONS: In this population of psoriasis patients with concomitant, moderate-to-severe nail psoriasis, long-term efficacy and improvement in signs and symptoms of nail disease were demonstrated after every-other-week ADA treatment, including incremental improvements in rate of total clearance of nail disease. No new safety risks were identified for patients receiving at least one ADA dose across 52 weeks.

Impact of ixekizumab on facial psoriasis and related quality of life measures in moderate-to-severe psoriasis patients: 12-week results from two phase III trials.

BACKGROUND: Facial psoriasis was reported in 17-68% of patients with psoriasis and shown to have a negative impact on patients' personal and health-related quality of life (HRQoL). OBJECTIVES: To explore the association of facial psoriasis with patients' HRQoL and to assess the relationship between ixekizumab (IXE) and improvement in facial psoriasis and changes in HRQoL. METHODS: This work reports the combined results of two phase III multicentre, randomized, double-blind, placebo-controlled, active-comparator trials in patients with moderate-to-severe psoriasis. Patients received placebo, etanercept (ETN; 50 mg twice weekly) or IXE [80 mg every 4 weeks (Q4W) or every 2 weeks (Q2W)] for up to 12 weeks following an initial 160-mg dose. HRQoL parameters were analysed based on facial psoriasis status at baseline using analysis of covariance models. Improvement was assessed as percentage of patients with no facial psoriasis. RESULTS: The combined database included 1133 patients with facial psoriasis and 1437 without. Patients treated with IXE whose facial psoriasis cleared had improved Dermatology Life Quality Index 0.1 responses (P < 0.01) compared with patients with facial psoriasis at Week 12. At Week 12, clearance of facial psoriasis compared with the presence of facial psoriasis was independently associated with significantly better improvement in Psoriasis Skin Appearance Bothersomeness scores in the IXE Q2W treatment group (P < 0.01). At Week 12, facial clearance and overall Psoriasis Area Severity Index (PASI) improvement were observed in significant numbers of patients treated with IXE compared with ETN and placebo. Facial psoriasis clearance at Week 12 in patients treated with IXE or ETN was positively associated with PASI75 and PASI90 achievement. CONCLUSION: Facial psoriasis had a larger negative impact on HRQoL than no facial psoriasis. Facial psoriasis clearance was associated with improved HRQoL. Significantly more IXE-treated patients had rapid facial clearance vs. ETN and PBO, which led to better clinical outcomes.

Apremilast for the treatment of moderate-to-severe palmoplantar psoriasis: results from a double-blind, placebo-controlled, randomized study.

BACKGROUND: Palmoplantar psoriasis is a variant of psoriasis vulgaris which can severely impair quality of life. OBJECTIVES: The main objectives of this double-blind, placebo-controlled, randomized study were to assess the efficacy and impact on quality of life and work productivity of apremilast for the treatment of moderate-to-severe palmoplantar psoriasis. METHODS: A total of 100 patients with moderate-to-severe palmoplantar psoriasis were randomized to either apremilast 30 mg bid or placebo for 16 weeks. At Week 16, all patients received apremilast 30 mg bid until Week 32. The primary endpoint was the proportion of patients who achieved a Palmoplantar Psoriasis Physician Global Assessment (PPPGA) of 0/1 at Week 16. RESULTS: There was no significant difference in the proportion of patients who achieved a PPPGA of 0/1 at Week 16 between patients randomized to apremilast (14%) and placebo (4%; P = 0.1595). After 32 weeks of treatment with apremilast, 24% of patients achieved a PPGA of 0/1. In addition, apremilast was superior to placebo in achieving Palmoplantar Psoriasis Area Severity Index (PPPASI) 75 (apremilast: 22%; placebo: 8%; P = 0.0499), in improving PPPASI (apremilast: -7.4 ± 7.1; placebo: -3.6 ± 5.9; P = 0.0167), Dermatology Life Quality Index score (apremilast: -4.3 ± 5.1; placebo: -0.8 ± 4.5; P = 0.0004) and in reducing activity impairment (apremilast: -11.0 ± 22.3; placebo: 2.5 ± 25.5; P = 0.0063). CONCLUSION: Despite the absence of a significant difference between apremilast and placebo in proportion of patients achieving a PPPGA of 0/1, the presence of significant differences observed for several secondary endpoints suggests that apremilast may have a role in the treatment of moderate-to-severe palmoplantar psoriasis.

Early relapse of psoriasis after stopping brodalumab: a retrospective cohort study in 77 patients.

BACKGROUND: Biological agents targeting IL-17 are very effective for clearing moderate to severe psoriasis. There is limited information regarding the frequency and pattern of psoriasis relapse upon treatment cessation. OBJECTIVE: To investigate the pattern of psoriasis recurrence in patients who were treated with brodalumab following Amgen's decision to stop the clinical programme in June 2015. MATERIALS AND METHODS: Between June 2015 and March 2016, we constructed a retrospective multicenter cohort study including patients who were treated with brodalumab in Amgen's protocols after the abrupt interruption of the drug development programme. The relapse was defined as the request of patient to initiate a new treatment after brodalumab withdrawal. RESULTS: Seventy-seven patients were followed up. At the time brodalumab treatment was stopped, 67 (87%) patients had reached PASI 90. After brodalumab discontinuation, all 77 patients relapsed after a follow-up of 9 months. The median time to relapse was 46 days (range 7-224 days). Concerning the type of relapse, 73 patients presented with plaque psoriasis, one patient presented with erythrodermic psoriasis, and three patients experienced pustular psoriasis. In seven patients who had no previous history of psoriatic arthritis (PsA), the relapse of psoriasis was associated with inflammatory joint pain suggestive of PsA. At week 36, eight patients who had a limited relapse were controlled with topical treatment, 43 patients received a biological agent, two patients were included in a clinical trial with an investigational drug and 15 patients were treated with conventional systemic agents. CONCLUSION: Abrupt cessation of brodalumab is associated with a rapid relapse of psoriasis with some patients experiencing a rebound. It seems not advisable to stop treatment with IL-17 receptor antagonists abruptly even in patients who experience complete clearance of psoriasis.

Impact of ixekizumab treatment on skin-related personal relationship difficulties in moderate-to-severe psoriasis patients: 12-week results from two Phase 3 trials.

BACKGROUND: Psoriasis symptoms may decrease quality of life for patients. Skin-related personal relationship difficulties in psoriasis patients are common, under-reported and poorly understood. OBJECTIVE: To assess the effect of ixekizumab (IXE) treatment on skin-related personal relationship difficulties in patients with moderate-to-severe psoriasis. METHODS: Pooled data (N = 2570) on skin-related relationship problems were obtained from two large phase 3 trials (UNCOVER-2 and UNCOVER-3) in patients with moderate-to-severe plaque psoriasis randomized to subcutaneous placebo (PBO, N = 361), etanercept (ETN; 50 mg twice weekly, N = 740), or 80 mg IXE as one injection every 4 (IXEQ4W, N = 733) or 2 weeks (IXEQ2W, N = 736) for 12 weeks, following a 160-mg initial dose. The Dermatology Life Quality Index (DLQI) Personal Relationships Domain (PRD) (Items 8 and 9) was used to assess how much the skin caused any personal relationship difficulties at weeks 0, 2, 4 and 12. Improvement was compared for IXE vs PBO and ETN using logistic models. Factors associated with improvement were assessed using multiple linear regressions. DLQI Item 9, assessing sexual difficulties, was also analysed separately. RESULTS: PRD scores (mean ± standard deviation) at baseline were similar across all treatment groups (PBO: 1.8 ± 1.9; ETN: 1.7 ± 1.8; IXEQ4W: 1.6 ± 1.8; IXEQ2W: 1.7 ± 1.8). Treatment with IXE rapidly and significantly improved the mean PRD score compared to PBO and ETN (P < 0.001 at all time points). Baseline PRD score was the strongest negative predictor of improvement. IXE enabled significantly more patients with moderate-to-severe plaque psoriasis to reduce their skin-related sexual difficulties at Week 12 compared to PBO (P < 0.001) or ETN (P < 0.001). CONCLUSION: Ixekizumab improves patient-reported skin-related PRD difficulties in patients with moderate-to-severe psoriasis.

Continuous dosing versus interrupted therapy with ixekizumab: an integrated analysis of two phase 3 trials in psoriasis.

BACKGROUND: Continuous treatment is recommended for patients with moderate-to-severe psoriasis; however, treatment may need to be interrupted in routine clinical practice. OBJECTIVE: To assess outcomes in patients continuously treated with ixekizumab versus those who interrupted therapy and were subsequently retreated with ixekizumab (IXE). METHODS: This analysis used data pooled from two phase 3 trials, UNCOVER-1 and UNCOVER-2. Patients were randomized to placebo (PBO), IXE every 4 (Q4W) or IXE every 2 weeks (Q2W) for 12 weeks. Patients with a static Physician's Global Assessment (sPGA) 0, 1 at Week 12 were rerandomized to IXEQ4W, IXE every 12 weeks (not presented) or PBO. We examined outcomes in patients who were continuously treated (IXEQ2W/IXEQ4W; IXEQ4W/IXEQ4W) or withdrawn (IXEQ2W/PBO; IXEQ4W/PBO), and in patients who were withdrawn and retreated with IXEQ4W for 24 weeks after disease relapse (sPGA ≥3). RESULTS: A total of 1226 treated patients achieved an sPGA 0, 1 at Week 12 and entered the maintenance phase; of these patients, 402 and 416 were rerandomized to PBO and IXEQ4W, respectively. Among patients interrupting treatment, 157 (82.2%) of IXEQ4W/PBO and 176 (83.4%) of IXEQ2W/PBO had an sPGA ≥3 by Week 60; median time to relapse was approximately 20 weeks irrespective of induction dose. At Week 60, continuously treated patients maintained high levels of PASI and sPGA responses (90.0% PASI 75 IXEQ2W/IXEQ4W; 81.9% sPGA 0, 1 IXEQ2W/IXEQ4W, non-responder imputation). After 24 weeks of retreatment with IXEQ4W (IXEQ2W/PBO/IXEQ4W and IXEQ4W/PBO/IXEQ4W), 87.0% (107 of 123) and 95.1% (97 of 102) (observed), respectively, of patients recaptured PASI 75 and 70.7% (104 of 147) and 82.3% (107 of 130) (observed) recaptured an sPGA 0, 1. Overall, adverse events in continuously treated and retreated patients were comparable. CONCLUSION: High levels of response were sustained with continuous ixekizumab treatment through 60 weeks. Most patients who were withdrawn experienced disease relapse, and most of those patients recaptured response after 24 weeks of retreatment.

Apremilast, an oral phosphodiesterase 4 inhibitor, improves patient-reported outcomes in the treatment of moderate to severe psoriasis: results of two phase III randomized, controlled trials.

BACKGROUND: Apremilast, an oral phosphodiesterase 4 inhibitor, has an acceptable safety profile and is effective for treatment of plaque psoriasis and psoriatic arthritis. OBJECTIVES: To evaluate the impact of apremilast on health-related quality of life (HRQOL), general functioning and mental health using patient-reported outcome (PRO) assessments among patients with moderate to severe plaque psoriasis in the ESTEEM 1 and 2 trials. METHODS: A total of 1255 patients were randomized (2 : 1) to apremilast 30 mg BID or placebo for 16 weeks; all received apremilast through Week 32. PRO assessments included the Dermatology Life Quality Index (DLQI), 36-Item Short-Form Health Survey version 2 mental/physical component summary scores (SF-36v2 MCS/PCS), Patient Health Questionnaire-8 (PHQ-8), EuroQol-5D (EQ-5D) and Work Limitations Questionnaire-25 (WLQ-25). Post hoc analyses examined relationships between Psoriasis Area and Severity Index (PASI) scores and PHQ-8 in the apremilast-treated population at Week 16. RESULTS: Treatment with apremilast improved all HRQOL PROs at Week 16 (vs. placebo), except the SF-36v2 PCS, and improvements were sustained through Week 32. Mean DLQI and SF-36v2 MCS improvements exceeded minimal clinically important differences. Changes at Week 16 in PHQ-8 and PASI were weakly correlated, and only 35.8% of patients who achieved a ≥75% reduction from baseline in PASI score (PASI-75) with apremilast treatment also achieved PHQ-8 scores of 0-4. CONCLUSIONS: Apremilast led to improvements in HRQOL PROs vs. placebo in patients with moderate to severe plaque psoriasis.

Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial.

BACKGROUND: Despite unmet need, 15 years have passed since a topical therapy with a new mechanism of action for atopic dermatitis (AD) has been approved. Janus kinase (JAK) inhibitor treatment effect via topical application in patients with AD is unknown. OBJECTIVES: Tofacitinib, a small-molecule JAK inhibitor, was investigated for the topical treatment of AD. METHODS: In this 4-week, phase IIa, randomized, double-blind, vehicle-controlled study (NCT02001181), 69 adults with mild-to-moderate AD were randomized 1:1 to 2% tofacitinib or vehicle ointment twice daily. Percentage change from baseline (CFB) in Eczema Area and Severity Index (EASI) score at week 4 was the primary end point. Secondary efficacy end points included percentage CFB in body surface area (BSA), CFB in EASI Clinical Signs Severity Sum Score, proportion of patients with Physician's Global Assessment (PGA) response and CFB in patient-reported pruritus. Safety, local tolerability and pharmacokinetics were monitored. RESULTS: The mean percentage CFB at week 4 in EASI score was significantly greater (P < 0·001) for tofacitinib (-81·7%) vs. vehicle (-29·9%). Patients treated with tofacitinib showed significant (P < 0·001) improvements vs. vehicle across all prespecified efficacy end points and for pruritus at week 4. Significant improvements in EASI, PGA and BSA were observed by week 1 and improvements in pruritus were observed by day 2. Safety/local tolerability were generally similar for both treatments, although more adverse events were observed for vehicle vs. tofacitinib. CONCLUSIONS: Tofacitinib ointment showed significantly greater efficacy vs. vehicle across end points, with early onset of effect and comparable safety/local tolerability to vehicle. JAK inhibition through topical delivery is potentially a promising therapeutic target for AD.

Efficacy and safety of follow-up field treatment of actinic keratosis with ingenol mebutate 0·015% gel: a randomized, controlled 12-month study.

BACKGROUND: Ingenol mebutate (IngMeb) is a novel patient-applied topical field therapy for actinic keratosis. OBJECTIVES: To demonstrate the efficacy and safety of follow-up IngMeb field treatment of actinic keratoses (AKs) present at 8 weeks after initial treatment or emerging in a previously cleared field. METHODS: In this phase III, randomized, double-blind study in patients with 4-8 clinically visible AKs within a contiguous 25-cm(2) treatment area on the face or scalp, all patients were treated initially with IngMeb 0·015% gel for three consecutive days. If lesions were present in the field at 8 weeks, or emerged at weeks 26 or 44, patients were randomized (2 : 1) to follow-up IngMeb or vehicle gel for three consecutive days. The main outcome was complete clearance rates of AKs 8 weeks after randomization. RESULTS: Of 450 patients who received initial treatment with IngMeb, 61·6% demonstrated complete clearance at 8 weeks. Patients with AKs present at 8 weeks or emerging at weeks 26 or 44 were randomized to IngMeb (n = 134) or vehicle (n = 69). IngMeb achieved a higher complete clearance rate than vehicle 8 weeks after randomization in AKs present at 8 weeks (46·7% vs. 18·4%; P < 0·01) and in emergent AKs (59·5% vs. 25·0%; P = 0·01). Based on those who completed 12 months of follow-up (n = 340), the overall 12-month clearance rate was estimated at 50·0%. Follow-up IngMeb treatment was well tolerated. CONCLUSIONS: This study demonstrated the long-term benefit of IngMeb 0·015% gel for initial and follow-up therapy of AKs.

Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2).

BACKGROUND: Apremilast, an oral phosphodiesterase 4 inhibitor, regulates immune responses associated with psoriasis. OBJECTIVES: ESTEEM 2 evaluated the efficacy and safety of apremilast 30 mg twice daily for moderate-to-severe plaque psoriasis. METHODS: This phase III, double-blind, placebo-controlled trial randomized adults to apremilast or placebo (2 : 1). At week 16, placebo patients switched to apremilast. At week 32, apremilast patients achieving ≥ 50% reduction in Psoriasis Area and Severity Index (PASI 50) were rerandomized (1 : 1) to continue apremilast or receive placebo. Upon loss of 50% of PASI improvement obtained at week 32, patients rerandomized to placebo resumed apremilast. RESULTS: The modified intention-to-treat population (full analysis set) included 137 placebo and 274 apremilast patients. At week 16, significantly more apremilast patients achieved PASI 75 (28·8%), PASI 50 (55·5%) and static Physician's Global Assessment score of 0 or 1 (20·4%) vs. placebo (5·8%, 19·7%, 4·4%, respectively; P < 0·001). Most patients rerandomized to apremilast at week 32 had a PASI 50 response at week 52 (80%). Patients treated with apremilast showed significant improvements in quality of life (as assessed by the Dermatology Life Quality Index) and pruritus at week 16 compared with placebo (P < 0·001). The exposure-adjusted incidence of adverse events did not increase with continued apremilast treatment for up to 52 weeks. The most common adverse events were nausea, diarrhoea, nasopharyngitis and upper respiratory tract infection. CONCLUSIONS: Apremilast was effective in the treatment of moderate-to-severe plaque psoriasis over 52 weeks.

Improvements in patient-reported outcomes in patients with psoriasis receiving etanercept plus topical therapies: results from REFINE.

BACKGROUND: The REFINE study examined the efficacy and safety of adding topical corticosteroid therapy to etanercept when stepping down from the initial dose of etanercept to the maintenance dose. Clinical responses were shown to be similar in patients who remained on etanercept 50 mg twice weekly (BIW) and those who received etanercept 50 mg once weekly (QW) plus topical therapies through week 24. OBJECTIVE: The purpose of this analysis was to evaluate the effect of treatment on health-related quality of life (HRQoL) for patients in REFINE. METHODS: All patients received etanercept 50 mg BIW for 12 weeks and were then randomized to etanercept 50 mg BIW or etanercept 50 mg QW plus topical corticosteroid as required to clear through week 24. HRQoL measures included the Dermatology Life Quality Index (DLQI), Treatment Satisfaction Questionnaire for Medication (TSQM) and the Economic Implications of Psoriasis Patient Questionnaire. No comparative testing was performed for this descriptive analysis. Missing data were imputed using the last observation carried forward. RESULTS: For 287 randomized patients (144 etanercept; 143 etanercept plus topical), the mean change [standard deviation (SD)] in DLQI from baseline to week 24 was 10.7 (7.8) for etanercept and 9.9 (6.9) for etanercept plus topical. Mean change (SD) in TSQM effectiveness, convenience, side-effects and global satisfaction was 27.1 (36.1), 14.8 (25.9), -0.7 (22.0) and 26.7 (32.5) for the etanercept arm and 32.5 (40.3), 18.5 (29.0), 1.3 (19.4) and 28.4 (35.9) for etanercept plus topical. Economic implications, including healthcare visits, employment status, work productivity, ability to perform daily activities and out-of-pocket expenses were similar between treatment arms. CONCLUSION: At week 24 of REFINE, measures of HRQoL were numerically similar in patients who stayed on etanercept 50 mg BIW and patients who received etanercept 50 mg QW plus topical therapies.

Long-term efficacy and safety of ustekinumab, with and without dosing adjustment, in patients with moderate-to-severe psoriasis: results from the PHOENIX 2 study through 5 years of follow-up.

BACKGROUND: Evaluation of the dosing flexibility and long-term efficacy of biological agents is limited. OBJECTIVES: To evaluate the long-term efficacy and safety of ustekinumab with and without dosing adjustment in the 5-year PHOENIX 2 study. METHODS: Patients were randomized to placebo or ustekinumab (45 or 90 mg) at weeks 0, 4, then every 12 weeks; patients receiving placebo crossed-over at week 12. Dosing adjustments were permitted at/beyond week 28 for early adjusters (weeks 28 or 40 per response); late adjusters (during long-term extension per investigator judgement); and nonadjusters (maintained randomized treatment throughout the study). Efficacy and safety were evaluated through weeks 244 and 264, respectively. RESULTS: In the overall population, 70% (849 of 1212) of ustekinumab-treated patients completed treatment through week 244, with high proportions of patients responding to the 45-mg and 90-mg doses, respectively: 75% improvement in Psoriasis Area and Severity Index (PASI 75) (76·5% and 78·6%) and PASI 90 (50·0% and 55·5%). Approximately 20% of patients were early adjusters, 30% were late adjusters and 50% were nonadjusters. Approximately half of the late adjusters initiated adjustments after already achieving PASI 75. Improved response was generally observed following dosing adjustments. Through week 264, safety event rates did not increase and event rates were generally comparable between dose groups and between patients with and without dosing adjustment. CONCLUSIONS: Treatment with ustekinumab for up to 5 years was safe and effective. Improved response was generally demonstrated following dosing adjustments; further investigations are required to quantify actual incremental benefits. The results also suggest that some patients may desire treatment goals beyond PASI 75.

A Randomized, blinded assessor study to Evaluate the efFIcacy and safety of etanercept 50 mg once weekly plus as Needed topical agent vs. Etanercept 50 mg twice weekly in patients with moderate to severe plaque psoriasis (REFINE).

BACKGROUND: Topical corticosteroids are used with systemic therapies for treatment of plaque psoriasis, but data from randomized clinical trials to document efficacy of combination therapy are lacking. OBJECTIVE: To evaluate efficacy and safety of adding topical corticosteroid therapy from the time that etanercept dosage is reduced from initial label dose [50 mg twice weekly (BIW)] to maintenance dose [50 mg once weekly (QW)]. METHODS: In this phase 3b, multicentre, randomized, open-label study, patients with moderate-to-severe plaque psoriasis received etanercept 50 mg BIW for 12 weeks, and then were randomized to etanercept 50 mg BIW or 50 mg QW plus topical agent as needed to achieve static physician global assessment (sPGA) status of clear for 12 weeks. Endpoints included percentage change in Psoriasis Area and Severity Index (PASI) score from week 12 to week 24 (primary endpoint); proportion of patients achieving 50% improvement in (PASI 50), PASI 75 and PASI 90; patients achieving sPGA of clear/almost clear; and change in affected body surface area (BSA). RESULTS: Mean difference [95% confidence interval (CI)] between etanercept arm (n = 140) and etanercept plus topical arm (n = 142) in change in PASI score from week 12 to week 24 was 16.2% (-3.5%, 35.8%). PASI response rates were similar between groups. Percentage (95% CI) of patients achieving sPGA status of clear/almost clear was 40.6% (32.5%, 48.6%) and 45.8% (37.6%, 54.0%) at week 12 for patients in etanercept and etanercept plus topical arms, respectively, and 53.5% (45.3%, 61.7%) and 45.4% (37.2%, 53.6%) at week 24. Difference (95% CI) between groups in change in affected BSA from week 12 to week 24 was 4.9% (-23.4%, 33.2%). CONCLUSION: Patients who received etanercept 50 mg QW at week 12 plus as-needed topical therapy and those who stayed on etanercept 50 mg BIW maintained clinical response through week 24 with no notable differences in PASI responses.

Changes in C-reactive protein in patients with moderate-to-severe psoriasis switched to adalimumab therapy after suboptimal response to etanercept, methotrexate or phototherapy.

BACKGROUND: Psoriasis treatment can lower levels of the inflammatory biomarker C-reactive protein (CRP). OBJECTIVE: Evaluate CRP changes in patients with chronic plaque psoriasis who switched to adalimumab following suboptimal response to previous therapies. METHODS: C-reactive protein was measured at screening and after 16 weeks of adalimumab treatment following discontinuation of previous therapies: etanercept (substudy E; n = 77), methotrexate (substudy M; n = 38) or narrow-band ultraviolet B phototherapy (substudy P; n = 27). Associations of CRP with baseline characteristics and efficacy measures were evaluated. RESULTS: Median CRP change at the final visit was -0.3 mg/L overall and -0.4, -0.3 and -0.3 mg/L in substudies E, M and P respectively. Clinical response [Physician Global Assessment (PGA) 'clear' or 'minimal'] was associated with greater CRP reductions vs. no response (PGA 'mild' or worse) overall (-0.4 vs. -0.3 mg/L) and in substudies E (-0.4 vs. -0.1 mg/L) and M (-0.5 vs. -0.2 mg/L), but not P (-0.1 vs. -0.4 mg/L). CRP decreases were, respectively, -0.4 and -0.3 mg/L in patients with and without a history of psoriatic arthritis and -0.1, -0.3 and -0.6 mg/L in normal weight, overweight and obese patients, respectively. CRP decreases after 16 weeks correlated positively (ß = 0.004) with percentage change in Psoriasis Area and Severity Index (PASI; P = 0.0398) and negatively (ß = -0.360) with baseline CRP (P < 0.0001). CONCLUSION: C-reactive protein levels decreased during adalimumab therapy in patients with psoriasis who experienced suboptimal response to previous therapies. Clinical response was associated with greater CRP reductions overall and in substudies E and M, but not P. CRP reductions correlated with percentage reductions in PASI.